4-oxo,1-4-dihydroquinoline m1 receptor positive allosteric modulators

ABSTRACT

The present invention is directed to compounds of formula (I) which are M1 receptor positive allosteric modulators and that are useful in the treatment of diseases in which the M1 receptor is involved, such as Alzheimer&#39;s disease, schizophrenia, pain or sleep disorders. The invention is also directed to pharmaceutical compositions comprising the compounds, and to the use of the compounds and compositions in the treatment of diseases mediated by the M1 receptor.

FIELD OF THE INVENTION

The invention is directed to a class of aryl pyridine compounds, theirsalts, pharmaceutical compositions comprising them and their use intherapy of the human body. In particular, the invention is directed to aclass of quinolizidinone compounds which are muscarinic M1 receptorpositive allosteric modulators, and hence are useful in the treatment ofAlzheimer's Disease and other diseases mediated by the muscarinic M1receptor.

BACKGROUND OF THE INVENTION

Alzheimer's Disease is a common neurodegenerative disease affecting theelderly, resulting in progressive memory impairment, loss of languageand visuospatial skills, and behavior deficits. Characteristics of thedisease include degeneration of cholinergic neurons in the cerebralcortex, hippocampus, basal forebrain, and other regions of the brain,neurofibrillary tangles, and accumulation of the amyloid β peptide (Aβ).Aβ is a 39-43 amino acid produced in the brain by processing of thebeta-amyloid precursor protein (APP) by the beta-amyloid proteincleaving enzyme (“beta secretase” or “BACE”) and gamma-secretase. Theprocessing leads to accumulation of Aβ in the brain.

Cholinergic neurotransmission involves the binding of acetylcholineeither to the nicotinic acetylcholine receptor (nAChR) or to themuscarinic acetylcholine receptor (mAChR). It has been hypothesized thatcholinergic hypofunction contributes to the cognitive deficits ofpatients suffering from Alzheimer's Disease. Consequently, acetylcholinesterase inhibitors, which inhibit acetylcholine hydrolysis, havebeen approved in the United States for use in the treatment of thecognitive impairments of Alzheimer's Disease patients. While acetylcholinesterase inhibitors have provided some cognitive enhancement inAlzheimer's Disease patients, the therapy has not been shown to changethe underlying disease pathology.

A second potential pharmacotherapeutic target to counteract cholinergichypofunction is the activation of muscarinic receptors. Muscarinicreceptors are prevalent throughout the body. Five distinct muscarinicreceptors (M1-M5) have been identified in mammals. In the centralnervous system, muscarinic receptors are involved in cognitive,behavior, sensory, motor and autonomic functions. The muscarinic M1receptor, which is prevalent in the cerebral cortex, hippocampus andstriatum, has been found to have a major role in cognitive processingand is believed to have a role in the pathophysiology of Alzheimer'sDisease. See Eglen et al, TRENDS in Pharmacological Sciences, 2001,22:8, 409-414. In addition, unlike acetyl cholinesterase inhibitors,which are known to provide only symptomatic treatment, M1 agonists alsohave the potential to treat the underlying disease mechanism ofAlzheimer's Disease. The cholinergic hypothesis of Alzheimer's Diseaseis linked to both β-amyloid and hyperphosphorylated tau protein.Formation of β-amyloid may impair the coupling of the muscarinicreceptor with G-proteins. Stimulation of the M1 muscarinic receptor hasbeen shown to increase formation of the neuroprotective αAPPs fragment,thereby preventing the formation of the Aβ peptide. Thus, M1 agonistsmay alter APP processing and enhance αAPPs secretion. See Fisher, Jpn JPharmacol, 2000, 84:101-112.

However, M1 ligands that have been developed and studied for Alzheimer'sDisease have produced side effects common to other muscarinic receptorligands, such as sweating, nausea and diarrhea. See Spalding et al, MolPharmacol, 2002, 61:6, 1297-1302.

The muscarinic receptors are known to contain one or more allostericsites, which may alter the affinity with which muscarinic ligands bindto the primary binding or orthosteric sites. See, e.g., S. Lazareno etal, Mol Pharmacol, 2002, 62:6, 1491-1505; S. Lazareno et al, MolPharmacol, 2000, 58, 194-207.

Thus the compounds of the invention, which are muscarinic M1 receptorpositive allosteric modulators, are believed to be useful in thetreatment of Alzheimer's Disease and other diseases mediated by themuscarinic M1 receptor.

SUMMARY OF THE INVENTION

The present invention is novel 4-oxo-1,4-dihydroquinoline compounds ofgeneric formula (I)

or a pharmaceutically acceptable salt thereof, which is useful as an M1receptor positive allosteric modulator.

The invention is further directed to methods of treating a patient(preferably a human) for diseases or disorders in which the M1 receptoris involved, such as Alzheimer's disease, cognitive impairment,schizophrenia, pain disorders and sleep disorders, by administering tothe patient a therapeutically effective amount of a compound of generalformula (I), or a pharmaceutically acceptable salt thereof. Theinvention is also directed to pharmaceutical compositions which includean effective amount of a compound of formula (I), or a pharmaceuticallyacceptable salt thereof, and a pharmaceutically acceptable carrier, andthe use of the compounds and pharmaceutical compositions of theinvention in the treatment of such diseases.

DETAILED DESCRIPTION OF THE INVENTION

In one embodiment, the invention is directed to compounds of generalformula (I)

and pharmaceutically acceptable salts thereof, whereinone or two of X¹, X², X³, X⁴ and X⁵ is NH, and the others are each CR³;R¹ and R² are each selected from the group consisting of

-   -   (1) hydrogen, or    -   (2) fluoro;        R³ is selected from the group consisting of    -   (1) hydrogen,    -   (2) halogen,    -   (3) cyano,    -   (4) —C₁₋₆-alkyl,    -   (5) —OC₁₋₆-alkyl,    -   (6) —C₃₋₈ cycloalkyl,    -   (7) —C₆₋₁₀ aryl,    -   (8) heteroaryl group having 5 to 12 ring atoms,    -   (9) —NR^(6A)R^(6B), or    -   (10) —S(O)_(m)—R^(5A),    -   wherein any alkyl, aryl, heteroaryl, and cycloalkyl R³ moiety is        optionally substituted with one or more    -   (a) halogen,    -   (b) hydroxy,    -   (c) cyano,    -   (d) —(CH₂)_(q)-aryl,    -   (e) —O—C₁₋₆ alkyl,    -   (f) —C₁₋₆ alkyl,    -   (g) —(CH₂)_(p)—NR^(6C)R^(6D),    -   (h) —C₃₋₈ cycloalkyl,    -   (i) heteroaryl group having 5 to 12 ring atoms,    -   (j) —C(═O)—OR^(5A),    -   (k) —C(═O)—R^(5A),    -   (l) —S(O)_(m)—R^(5A),    -   (m) —C(═O)—NR^(6A)R^(6B),    -   (n) —NR^(5A)SO₂—R^(5B),    -   (o) —NR^(5A)C(═O)R^(5B),    -   (p) —NR^(5A)C(═O)—O—R^(5B), or    -   and wherein said alkyl, aryl or heteroaryl moiety is optionally        substituted with one or more    -   (i) halogen,    -   (ii) hydroxy, or    -   (iii) cyano;        R⁴ is selected from the group consisting of    -   (1) hydrogen,    -   (2) —C₁₋₆ alkyl, or    -   (3) —CH₂-aryl,    -   wherein said R³ alkyl or aryl moiety is optionally substituted        with one or more        -   (a) halogen,        -   (b) cyano, and        -   (c) —O—C₁₋₆ alkyl, wherein said alkyl is optionally            substituted with one or more halo;            R^(5A) and R^(5B) are independently selected from the group            consisting of    -   (1) hydrogen,    -   (2) —C₁₋₆ alkyl, or    -   (3) —(CH₂)_(n)-aryl,    -   wherein said R^(5A) or R^(5B) alkyl or aryl moiety is optionally        substituted with one or more        -   (a) halogen,        -   (b) cyano, or        -   (c) —O—C₁₋₆ alkyl, wherein said alkyl is optionally            substituted with one or more halo;            R^(6A), R^(6B), R^(6C) and R^(6D) are selected from the            group consisting of    -   (1) hydrogen,    -   (2) —C₁₋₆ alkyl, or    -   (3) —C₃₋₆ cycloalkyl,        or R^(6A) and R^(6B), or R^(6C) and R^(6D) are linked together        with the nitrogen to which they are both attached to form a 3-6        membered carbocyclic ring, wherein one or two of the ring carbon        atoms is replaced by a nitrogen, oxygen or sulfur;        m is 0, 1 or 2;        n is 0 or 1;        p is 0 or 1; and        q is 0 or 1.

In particular embodiments of compounds of formula (I), one of X¹, X²,X³, X⁴ and X⁵ is NH, and the others are each CR³. Typically, three ofthe CR³ groups are CH and the CR³ in the remaining CR³ group is otherthan hydrogen.

In other embodiments of compounds of formula (I), two of X¹, X², X³, X⁴and X⁵ is NH, and the others are each CR³. Typically, two of the CR³groups are CH and the R³ in the remaining CR³ group is other thanhydrogen.

In preferred embodiments, when R³ is other than hydrogen, R³ is selectedfrom

-   -   (1) —C₆₋₁₀ aryl (preferably phenyl), or    -   (2) heteroaryl group having 5 to 12 ring atoms.

In one subgroup, the heteroaryl R³ groups include groups having 5 or 6ring atoms and a single heteroatom, which is nitrogen. Exemplaryheteroaryl groups in this embodiment are pyridyl and pyrrolyl.

Another subgroup of R³ heteroaryl groups have 5 or 6 ring atoms and twoheteroatoms, which are selected from sulfur and nitrogen. Exemplaryheteroaryl groups in this embodiment are pyrazolyl, pyrimidinyl,imidazolyl, thienyl and isothiazolyl.

Another subgroup of R³ heteroaryl groups have 9 or 10 ring atoms and twoheteroatoms, which are selected from oxygen, sulfur and nitrogen.Exemplary heteroaryl groups in this embodiment are benzoxazolyl,benzothiazolyl and quinoxalinyl.

When R³ is aryl or heteroaryl, in certain embodiments the aryl orheteroaryl moiety is substituted with one or more

-   -   (a) halogen,    -   (b) cyano,    -   (c) —O—C₁₋₆ alkyl (preferably —O—C₁₋₃ alkyl), wherein the alkyl        is optionally substituted with one or more fluoro,    -   (d) —C₁₋₆ alkyl (preferably —C₁₋₃ alkyl), wherein the alkyl is        optionally substituted with one or more fluoro,    -   (e) —NR^(6C)R^(6D),    -   (f) —C(═O)—OR^(5A),    -   (g) —C(═O)—R^(5A),    -   (h) —S(O)_(m)—R^(5A),    -   (i) —C(═O)—NR^(6A)R^(6B),    -   (j) —NR^(5A)SO₂—R^(5B),    -   (k) —NR^(5A)C(═O)R^(5B), or    -   (l) —NR^(5A)C(═O)—O—R^(5B).

In particular embodiments of compounds of formula (I), one of R¹ and R²is fluoro and the other is hydrogen. In other embodiments of compoundsof formula (I), both of R¹ and R² are fluoro. In other embodiments ofcompounds of formula (I), both of R¹ and R² are hydrogen.

In particular embodiments of the compounds of formula (I), R⁴ ishydrogen.

In one embodiment, the invention is directed to methods of treating apatient (preferably a human) for diseases in which the M1 receptor isinvolved, such as Alzheimer's Disease, cognitive impairment,schizophrenia, pain disorders and sleep disorders, by administering tothe patient a therapeutically effective amount of a compound of generalformula (I).

The invention is also directed to the use of a compound of formula (I)for treating diseases or disorders in which the M1 receptor is involved,such as Alzheimer's disease, cognitive impairment, schizophrenia, paindisorders and sleep disorders.

The invention is also directed to medicaments or pharmaceuticalcompositions for treating diseases or disorders in which the M1 receptoris involved, such as Alzheimer's disease, cognitive impairment,schizophrenia, pain disorders and sleep disorders, which comprise acompound of formula (I), or a pharmaceutically acceptable salt thereof,and a pharmaceutically acceptable carrier.

The invention is further directed to a method for the manufacture of amedicament or a composition for treating diseases or disorders in whichthe M1 receptor is involved, such as Alzheimer's disease, cognitiveimpairment, schizophrenia, pain disorders and sleep disorders,comprising combining a compound of formula (I) with one or morepharmaceutically acceptable carriers.

Within the genus of compounds of formula (I), there is a sub-genus ofcompounds of formula (II):

and pharmaceutically acceptable salts thereof, wherein R¹, R², R³ and R⁴are as defined above. Preferably, R³ is other than hydrogen.

Within the genus of compounds of formula (I), there is a sub-genus ofcompounds of formula (III):

and pharmaceutically acceptable salts thereof, wherein R¹, R² and R⁴ areas defined above, and R^(3A) and R^(3B) group are from the groupdescribed above for R³. Preferably, at least one of R^(3A) and R^(3B) isother than hydrogen.

Within the genus of compounds of formula (I), there is a sub-genus ofcompounds of formula (IV):

and pharmaceutically acceptable salts thereof, wherein R¹, R², R³ and R⁴are as defined above. Preferably, R³ is other than hydrogen.

Within the genus of compounds of formula (I), there is a sub-genus ofcompounds of formula (V):

and pharmaceutically acceptable salts thereof, wherein R¹, R² and R⁴ areas defined above, and R^(3A) and R^(3B) group are from the groupdescribed above for R³. Preferably, at least one of R^(3A) and R^(3B) isother than hydrogen.

Within the genus of compounds of formula (I), there is a sub-genus ofcompounds of formula (VI):

and pharmaceutically acceptable salts thereof, wherein R¹, R², R³ and R⁴are as defined above. Preferably, R³ is other than hydrogen.

Within the genus of compounds of formula (I), there is a sub-genus ofcompounds of formula (VII):

and pharmaceutically acceptable salts thereof, wherein R¹, R², R³ and R⁴are as defined above. Preferably, R³ is other than hydrogen.

Within the genus of compounds of formula (I), there is a sub-genus ofcompounds of formula (VIII):

and pharmaceutically acceptable salts thereof, wherein R¹, R², R³ and R⁴are as defined above. Preferably, R³ is other than hydrogen.

Within the genus of compounds of formula (I), there is a sub-genus ofcompounds of formula (IX):

and pharmaceutically acceptable salts thereof, wherein R¹, R², R³ and R⁴are as defined above. Preferably, R³ is other than hydrogen.

Specific embodiments of formula (I) are described herein as Examples1-373, or a pharmaceutically acceptable salt thereof.

The invention is also directed to methods of treating a patient(preferably a human) for diseases or disorders in which the M1 receptoris involved, such as Alzheimer's Disease, cognitive impairment,schizophrenia, pain disorders and sleep disorders, by administering tothe patient a therapeutically effective amount of a compound of formulae(II) to (IX), or a pharmaceutically acceptable salt thereof.

The invention is also directed to the use of a compound of formulae (II)to (IX) for treating a disease or disorder in which the M1 receptor isinvolved, such as Alzheimer's Disease, cognitive impairment,schizophrenia, pain disorders and sleep disorders, by administering tothe patient a compound of formulae (II) to (IX), or a pharmaceuticallyacceptable salt thereof.

The invention is also directed to medicaments or pharmaceuticalcompositions for the treatment of diseases or disorders in a patient(preferably a human) in which the M1 receptor is involved, such asAlzheimer's Disease, cognitive impairment, schizophrenia, paindisorders, and sleep disorders, which comprise a compound of formulae(II) to (IX), or a pharmaceutically acceptable salt thereof, and apharmaceutically acceptable carrier.

The invention is also directed to a method for the manufacture of amedicament or a pharmaceutical composition for treating diseases inwhich M1 receptor is involved, such as Alzheimer's Disease, cognitiveimpairment, schizophrenia, pain disorders, and sleep disorders, bycombining a compound of formulae (II) to (IX), or a pharmaceuticallyacceptable salt thereof, with a pharmaceutically acceptable carrier.

Where a variable occurs more than once in any of Formulas (I) to (IX) orin a substituent thereof, the individual occurrences of that variableare independent of each other, unless otherwise specified.

As used herein, in particular in the definitions of R², R³, R^(4A) andR^(4B), the term “alkyl,” by itself or as part of another substituent,means a saturated straight or branched chain hydrocarbon radical havingthe number of carbon atoms designated (e.g., C₁₋₁₀ alkyl means an alkylgroup having from one to ten carbon atoms). Preferred alkyl groups foruse in the invention are C₁₋₆ alkyl groups, having from one to sixatoms. Exemplary alkyl groups include methyl, ethyl, n-propyl,isopropyl, n-butyl, isobutyl, tert-butyl, pentyl, hexyl, and the like.C₀ alkyl means a bond.

As used herein, in particular in the definition of R², the term“alkenyl,” by itself or as part of another substituent, means a straightor branched chain hydrocarbon radical having a single carbon-carbondouble bond and the number of carbon atoms designated (e.g., C₂₋₁₀alkenyl means an alkenyl group having from two to ten carbon atoms).Preferred alkenyl groups for use in the invention are C₂₋₆ alkenylgroups, having from two to six carbon atoms. Exemplary alkenyl groupsinclude ethenyl and propenyl.

As used herein, in particular in the definition of R², the term“alkynyl,” by itself or as part of another substituent, means a straightor branched chain hydrocarbon radical having a single carbon-carbontriple bond and the number of carbon atoms designated (e.g., C₂₋₁₀alkynyl means an alkynyl group having from two to ten carbon atoms).Preferred alkynyl groups for use in the invention are C₂₋₆ alkynylgroups, having from two to six carbon atoms. Exemplary alkenyl groupsinclude ethynyl and propynyl.

As used herein, in particular in the definitions of R², R³, R^(4A) andR^(4B), the term “aryl,” by itself or as part of another substituent,means an aromatic cyclic hydrocarbon radical. Preferred aryl groups havefrom six to ten carbons atoms. The term “aryl” includes multiple ringsystems as well as single ring systems. Preferred aryl groups for use inthe invention include phenyl and naphthyl.

The term “aryl” also includes fused cyclic hydrocarbon rings which arepartially aromatic (i.e., one of the fused rings is aromatic and theother is non-aromatic). An exemplary aryl group which is partiallyaromatic is indanyl.

As used herein, the term “halo” or “halogen” includes fluoro, chloro,bromo and iodo.

As used herein, in particular in the definition of R², the term“heteroaryl,” by itself or as part of another substituent, means acyclic or polycyclic group having ring carbon atoms and at least onering heteroatom (O, N or S), wherein at least one of the constituentrings is aromatic. Exemplary heteroaryl groups for use in the inventioninclude carbazolyl, carbolinlyl, chromenyl, cinnolinyl, furanyl,benzofuranyl, benzofurazanyl, isobenzofuranyl, imidazolyl,benzimidazolyl, benzimidazolonyl, indazolyl, indolyl, isoindolyl,indolinyl, indolazinyl, indynyl, oxadiazolyl, oxazolyl, benzoxazolyl,isoxazolyl, pyranyl, pyrazinyl, pyrazolyl, benzopyrazolyl, pyridazinyl,pyridyl, pyrimidinyl, pyrrolyl, quinolyl, isoquinolyl, tetrazolyl,thiazolyl, isothiazolyl, thiadiazolyl, thienyl, benzothioenyl,benzothiazolyl, quinoxalinyl, triazinyl and triazolyl, and N-oxidesthereof.

Preferred R² heteroaryl groups have from 5 to 12 ring atoms. In one suchembodiment, the heteroaryl groups have 5 or 6 ring atoms.

For example, one subgroup of R² heteroaryl groups have 5 or 6 ring atomsand a single heteroatom, which is nitrogen. Exemplary heteroaryl groupsin this embodiment are pyridyl and pyrrolyl.

Another subgroup of R² heteroaryl groups have 5 or 6 ring atoms and twoheteroatoms, which are selected from sulfur and nitrogen. Exemplaryheteroaryl groups in this embodiment are pyrazolyl, imidazolyl, thienyland isothiazolyl.

Another subgroup of R² heteroaryl groups have 7 or 8 ring atoms and twoheteroatoms, which are selected from oxygen, sulfur and nitrogen.Exemplary heteroaryl groups in this embodiment are benzoxazolyl,benzothiazolyl and quinoxalinyl.

The term “heteroaryl” also includes fused cyclic heterocyclic ringswhich are partially aromatic (i.e., one of the fused rings is aromaticand the other is non-aromatic). An exemplary heteroaryl group which ispartially aromatic is benzodioxol.

When a heteroaryl group as defined herein is substituted, thesubstituent may be bonded to a ring carbon atom of the heteroaryl group,or on a ring heteroatom (i.e., a nitrogen, oxygen or sulfur), which hasa valence which permits substitution. Preferably, the substituent isbonded to a ring carbon atom. Similarly, when a heteroaryl group isdefined as a substituent herein, the point of attachment may be at aring carbon atom of the heteroaryl group, or on a ring heteroatom (i.e.,a nitrogen, oxygen or sulfur), which has a valence which permitsattachment. Preferably, the attachment is at a ring carbon atom.

The compounds of the invention may have one or more asymmetric centers.Compounds with asymmetric centers give rise to enantiomers (opticalisomers), diastereomers (configurational isomers) or both, and it isintended that all of the possible enantiomers and diastereomers inmixtures and as pure or partially purified compounds are included withinthe scope of this invention. The present invention is meant to encompassall such isomeric forms of the compounds of formulae (I) to (IX).

Formulae (I) to (IX) are shown above without a definite stereochemistryat certain positions. The present invention includes all stereoisomersof formulae (I) to (VI) and pharmaceutically acceptable salts thereof.

The independent syntheses of the enantiomerically or diastereomericallyenriched compounds, or their chromatographic separations, may beachieved as known in the art by appropriate modification of themethodology disclosed herein. Their absolute stereochemistry may bedetermined by the x-ray crystallography of crystalline products orcrystalline intermediates that are derivatized, if necessary, with areagent containing an asymmetric center of known absolute configuration.

If desired, racemic mixtures of the compounds may be separated so thatthe individual enantiomers or diastereomers are isolated. The separationcan be carried out by methods well known in the art, such as thecoupling of a racemic mixture of compounds to an enantiomerically purecompound to form a diastereomeric mixture, followed by separation of theindividual diastereomers by standard methods, such as fractionalcrystallization or chromatography. The coupling reaction is often theformation of salts using an enantiomerically pure acid or base. Thediastereomeric derivatives may then be converted to the pure enantiomersby cleavage of the added chiral residue. The racemic mixture of thecompounds can also be separated directly by chromatographic methodsusing chiral stationary phases, which methods are well known in the art.

Alternatively, any enantiomer or diastereomer of a compound may beobtained by stereoselective synthesis using optically pure startingmaterials or reagents of known configuration by methods well known inthe art.

The compounds of the invention may be prepared according to thefollowing reaction Schemes, in which variables areas defined before orare derived, using readily available starting materials, from reagentsand conventional synthetic procedures. It is also possible to usevariants which are themselves known to those of ordinary skill inorganic synthesis art, but are not mentioned in greater detail.

Ethyl 8-fluoro-4-oxo-1,4-dihydroquinoline-3-carboxylate 1 is a knowncompound (Scheme 1) and can be alkylated with the appropriate halide ormesylate such as 2 in a solvent like DMF using a base like potassiumcarbonate. Ethyl ester 3 can undergo hydrolysis using a base likelithium hydroxide in a solvent like dioxane. Acid 4 can undergo a crosscoupling with boronic acid 5 using a metal like palladium (0), aphosphine ligand such as tri tert-butyl phosphine, with a base likecesium carbonate in a solvent like THF, with conventional or microwaveheating to afford Example 1.

As shown in Scheme 2, ethyl ester 6 can undergo a cross-coupling similarto Scheme 1 with a boronate ester such as 7 as shown to afford compound8. In this case, the tert-butoxycarbonyl group present in 7 may fall offunder the reaction conditions, or can be removed using an acid such asHCl in a solvent like ethyl acetate. Pyrazole 8 may be alkylated with analkyl halide such a ethyl bromide using a base like sodium hydride inDMF. Subsequent hydrolysis of the ethyl ester using a base like sodiumhydroxide affords Example 2.

Carboxylic acid 9 can undergo an N-arylation reaction with a heterocyclelike imidazole in the presence of a copper catalyst like copper iodide,a ligand such as 10, employing a base like cesium carbonate, in asolvent like N-methylpyrrolidone, with conventional or microwave heatingto afford Example 3.

The chloride in acid 11 may be directly displaced by nucleophiles asshown in Scheme 4. Heating 11 in a solvent like DMSO with an amine suchas piperidine affords Example 372. Displacement of the chloride with asulfur nucleophile such as sodium thiomethoxide in DMSO, followed bysubsequent oxidation of 12 with a reagent like oxone in methanol-wateraffords Example 373.

The present invention also provides a method for the synthesis ofcompounds useful as intermediates in the preparation of compounds of theinvention

During any of the above synthetic sequences it may be necessary ordesirable to protect sensitive or reactive groups on any of themolecules concerned. This may be achieved by means of conventionalprotecting groups, such as those described in Protective Groups inOrganic Chemistry, ed. J. F. W. McOmie, Plenum Press, 1973, and T. W.Greene & P/G. M. Wuts, Protective Groups in Organic Synthesis, JohnWiley & Sons, 1991. The protecting groups may be removed at a convenientsequent stage using methods known from the art.

Specific embodiments of the compounds of the invention, and methods ofmaking them, are described in the Examples herein.

The term “substantially pure” means that the isolated material is atleast 90% pure, and preferably 95% pure, and even more preferably 99%pure as assayed by analytical techniques known in the art.

As used herein, the term “muscarinic M1 receptor” refers to one of thefive subtypes of the muscarinic acetylcholine receptor, which is fromthe superfamily of G-protein coupled receptors. The family of muscarinicreceptors is described, for example, in Pharmacol Ther, 1993,58:319-379; Eur J Pharmacol, 1996, 295:93-102, and Mol Pharmacol, 2002,61:1297-1302. The muscarinic receptors are known to contain one or moreallosteric sites, which may alter the affinity with which muscarinicligands bind to the primary binding or orthosteric sites. See, e.g., S.Lazareno et al, Mol Pharmacol, 2002, 62:6, 1491-1505.

As used herein, the terms “positive allosteric modulator” and“allosteric potentiator” are used interchangeably, and refer to a ligandwhich interacts with an allosteric site of a receptor to activate theprimary binding site. The compounds of the invention are positiveallosteric modulators of the muscarinic M1 receptor. For example, amodulator or potentiator may directly or indirectly augment the responseproduced by the endogenous ligand (such as acetylcholine or xanomeline)at the orthosteric site of the muscarinic M1 receptor in an animal, inparticular, a human.

The actions of ligands at allosteric receptor sites may also beunderstood according to the “allosteric ternary complex model,” as knownby those skilled in the art. The allosteric ternary complex model isdescribed with respect to the family of muscarinic receptors in Birdsallet al, Life Sciences, 2001, 68:2517-2524. For a general description ofthe role of allosteric binding sites, see Christopoulos, Nature Reviews:Drug Discovery, 2002, 1:198-210.

It is believed that the compounds of the invention bind to an allostericbinding site that is distinct from the orthosteric acetylcholine site ofthe muscarinic M1 receptor, thereby augmenting the response produced bythe endogenous ligand acetylcholine at the orthosteric site of the M1receptor. It is also believed that the compounds of the invention bindto an allosteric site which is distinct from the xanomeline site of themuscarinic M1 receptor, thereby augmenting the response produced by theendogenous ligand xanomeline at the orthosteric site of the M1 receptor.

The term “pharmaceutically acceptable salts” refers to salts preparedfrom pharmaceutically acceptable non-toxic bases or acids includinginorganic or organic bases and inorganic or organic acids. The compoundsof the invention may be mono, di or tris salts, depending on the numberof acid functionalities present in the free base form of the compound.Free bases and salts derived from inorganic bases include aluminum,ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganicsalts, manganous, potassium, sodium, zinc, and the like.

Salts in the solid form may exist in more than one crystal structure,and may also be in the form of hydrates. Salts derived frompharmaceutically acceptable organic non-toxic bases include salts ofprimary, secondary, and tertiary amines, substituted amines includingnaturally occurring substituted amines, cyclic amines, and basic ionexchange resins, such as arginine, betaine, caffeine, choline,N,N′-dibenzylethylene-diamine, diethylamine, 2-diethylaminoethanol,2-dimethylaminoethanol, ethanolamine, ethylenediamine,N-ethyl-morpholine, N-ethylpiperidine, glucamine, glucosamine,histidine, hydrabamine, isopropylamine, lysine, methylglucamine,morpholine, piperazine, piperidine, polyamine resins, procaine, purines,theobromine, triethylamine, trimethylamine, tripropylamine,tromethamine, and the like.

When the compound of the present invention is basic, salts may beprepared from pharmaceutically acceptable non-toxic acids, includinginorganic and organic acids. Such acids include acetic, trifluoroacetic,benzenesulfonic, benzoic, camphorsulfonic, citric, ethanesulfonic,fumaric, gluconic, glutamic, hydrobromic, hydrochloric, isethionic,lactic, maleic, malic, mandelic, methanesulfonic, mucic, nitric, pamoic,pantothenic, phosphoric, succinic, sulfuric, tartaric, p-toluenesulfonicacid, and the like.

The present invention is directed to the use of the compounds offormulas (I) to (IX) disclosed herein as M1 allosteric modulators in apatient or subject such as a mammal in need of such activity, comprisingthe administration of an effective amount of the compound. In additionto humans, a variety of other mammals can be treated according to themethod of the present invention.

The compounds of the present invention have utility in treating orameliorating Alzheimer's disease. The compounds may also be useful intreating or ameliorating other diseases mediated by the muscarinic M1receptor, such as schizophrenia, sleep disorders, pain disorders(including acute pain, inflammatory pain and neuropathic pain) andcognitive disorders (including mild cognitive impairment). Otherconditions that may be treated by the compounds of the invention includeParkinson's Disease, pulmonary hypertension, chronic obstructivepulmonary disease (COPD), asthma, urinary incontinence, glaucoma,schizophrenia, Trisomy 21 (Down Syndrome), cerebral amyloid angiopathy,degenerative dementia, Hereditary Cerebral Hemorrhage with Amyloidosisof the Dutch-Type (HCHWA-D), Creutzfeld-Jakob disease, prion disorders,amyotrophic lateral sclerosis, progressive supranuclear palsy, headtrauma, stroke, pancreatitis, inclusion body myositis, other peripheralamyloidoses, diabetes, autism and atherosclerosis.

In preferred embodiments, the compounds of the invention are useful intreating Alzheimer's Disease, cognitive disorders, schizophrenia, paindisorders and sleep disorders. For example, the compounds may be usefulfor the prevention of dementia of the Alzheimer's type, as well as forthe treatment of early stage, intermediate stage or late stage dementiaof the Alzheimer's type.

Potential schizophrenia conditions or disorders for which the compoundsof the invention may be useful include one or more of the followingconditions or diseases: schizophrenia or psychosis includingschizophrenia (paranoid, disorganized, catatonic or undifferentiated),schizophreniform disorder, schizoaffective disorder, delusionaldisorder, brief psychotic disorder, shared psychotic disorder, psychoticdisorder due to a general medical condition and substance-induced ordrug-induced (phencyclidine, ketamine and other dissociativeanaesthetics, amphetamine and other psychostimulants and cocaine)psychosispsychotic disorder, psychosis associated with affectivedisorders, brief reactive psychosis, schizoaffective psychosis,“schizophrenia-spectrum” disorders such as schizoid or schizotypalpersonality disorders, or illness associated with psychosis (such asmajor depression, manic depressive (bipolar) disorder, Alzheimer'sdisease and post-traumatic stress syndrome), including both the positiveand the negative symptoms of schizophrenia and other psychoses;cognitive disorders including dementia (associated with Alzheimer'sdisease, ischemia, multi-infarct dementia, trauma, vascular problems orstroke, HIV disease, Parkinson's disease, Huntington's disease, Pick'sdisease, Creutzfeldt-Jacob disease, perinatal hypoxia, other generalmedical conditions or substance abuse); delirium, amnestic disorders orage related cognitive decline.

In another specific embodiment, the present invention provides a methodfor treating schizophrenia or psychosis comprising: administering to apatient in need thereof an effective amount of a compound of the presentinvention. Particular schizophrenia or psychosis pathologies areparanoid, disorganized, catatonic or undifferentiated schizophrenia andsubstance-induced psychotic disorder. At present, the text revision ofthe fourth edition of the Diagnostic and Statistical Manual of MentalDisorders (DSM-IV-TR) (2000, American Psychiatric Association,Washington D.C.) provides a diagnostic tool that includes paranoid,disorganized, catatonic or undifferentiated schizophrenia andsubstance-induced psychotic disorder. As used herein, the term“schizophrenia or psychosis” includes treatment of those mentaldisorders as described in DSM-IV-TR. The skilled artisan will recognizethat there are alternative nomenclatures, nosologies and classificationsystems for mental disorders, and that these systems evolve with medicaland scientific progress. Thus the term “schizophrenia or psychosis” isintended to include like disorders that are described in otherdiagnostic sources.

Examples of combinations of the compounds include combinations withagents for the treatment of schizophrenia, for example in combinationwith sedatives, hypnotics, anxiolytics, antipsychotics, antianxietyagents, cyclopyrrolones, imidazopyridines, pyrazolopyrimidines, minortranquilizers, melatonin agonists and antagonists, melatonergic agents,benzodiazepines, barbiturates, 5HT-2 antagonists, and the like, such as:adinazolam, allobarbital, alonimid, aiprazolam, amisulpride,amitriptyline, amobarbital, amoxapine, aripiprazole, bentazepam,benzoctamine, brotizolam, bupropion, busprione, butabarbital,butalbital, capuride, carbocloral, chloral betaine, chloral hydrate,clomipramine, clonazepam, cloperidone, clorazepate, chlordiazepoxide,clorethate, chlorpromazine, clozapine, cyprazepam, desipramine,dexclamol, diazepam, dichloralphenazone, divalproex, diphenhydramine,doxepin, estazolam, ethchlorvynol, etomidate, fenobam, flunitrazepam,flupentixol, fluphenazine, flurazepam, fluvoxamine, fluoxetine,fosazepam, glutethimide, halazepam, haloperidol, hydroxyzine,imipramine, lithium, lorazepam, lormetazepam, maprotiline, mecloqualone,melatonin, mephobarbital, meprobamate, methaqualone, midaflur,midazolam, nefazodone, nisobamate, nitrazepam, nortriptyline,olanzapine, oxazepam, paraldehyde, paroxetine, pentobarbital, perlapine,perphenazine, phenelzine, phenobarbital, prazepam, promethazine,propofol, protriptyline, quazepam, quetiapine, reclazepam, risperidone,roletamide, secobarbital, sertraline, suproelone, temazepam,thioridazine, thiothixene, tracazolate, tranylcypromaine, trazodone,triazolam, trepipam, tricetamide, triclofos, trifluoperazine,trimetozine, trimipramine, uldazepam, venlafaxine, zaleplon,ziprasidone, zolazepam, zolpidem, and salts thereof, and combinationsthereof, and the like, or the subject compound may be administered inconjunction with the use of physical methods such as with light therapyor electrical stimulation.

In another embodiment, the subject compound may be employed incombination with levodopa (with or without a selective extracerebraldecarboxylase inhibitor such as carbidopa or benserazide),anticholinergics such as biperiden (optionally as its hydrochloride orlactate salt) and trihexyphenidyl (benzhexol)hydrochloride, COMTinhibitors such as entacapone, MOA-B inhibitors, antioxidants, A2aadenosine receptor antagonists, cholinergic agonists, NMDA receptorantagonists, serotonin receptor antagonists and dopamine receptoragonists such as alentemol, bromocriptine, fenoldopam, lisuride,naxagolide, pergolide and pramipexole. It will be appreciated that thedopamine agonist may be in the form of a pharmaceutically acceptablesalt, for example, alentemol hydrobromide, bromocriptine mesylate,fenoldopam mesylate, naxagolide hydrochloride and pergolide mesylate.

In another embodiment, the subject compound may be employed incombination with a compound from the phenothiazine, thioxanthene,heterocyclic dibenzazepine, butyrophenone, diphenylbutylpiperidine andindolone classes of neuroleptic agent. Suitable examples ofphenothiazines include chlorpromazine, mesoridazine, thioridazine,acetophenazine, fluphenazine, perphenazine and trifluoperazine. Suitableexamples of thioxanthenes include chlorprothixene and thiothixene. Anexample of a dibenzazepine is clozapine. An example of a butyrophenoneis haloperidol. An example of a diphenylbutylpiperidine is pimozide. Anexample of an indolone is molindolone. Other neuroleptic agents includeloxapine, sulpiride and risperidone. It will be appreciated that theneuroleptic agents when used in combination with the subject compoundmay be in the form of a pharmaceutically acceptable salt, for example,chlorpromazine hydrochloride, mesoridazine besylate, thioridazinehydrochloride, acetophenazine maleate, fluphenazine hydrochloride,flurphenazine enathate, fluphenazine decanoate, trifluoperazinehydrochloride, thiothixene hydrochloride, haloperidol decanoate,loxapine succinate and molindone hydrochloride. Perphenazine,chlorprothixene, clozapine, haloperidol, pimozide and risperidone arecommonly used in a non-salt form. Thus, the subject compound may beemployed in combination with acetophenazine, alentemol, aripiprazole,amisuipride, benzhexyl, bromocriptine, biperiden, chiorpromazine,chlorprothixene, clozapine, diazepam, fenoldopam, fluphenazine,haloperidol, levodopa, levodopa with benserazide, levodopa withcarbidopa, lisuride, loxapine, mesoridazine, molindolone, naxagolide,olanzapine, pergolide, perphenazine, pimozide, pramipexole, quetiapine,risperidone, sulpiride, tetrabenazine, frihexyphenidyl, thioridazine,thiothixene, trifluoperazine or ziprasidone.

Potential sleep conditions or disorders for which the compounds of theinvention may be useful include enhancing sleep quality; improving sleepquality; augmenting sleep maintenance; increasing the value which iscalculated from the time that a subject sleeps divided by the time thata subject is attempting to sleep; decreasing sleep latency or onset (thetime it takes to fall asleep); decreasing difficulties in fallingasleep; increasing sleep continuity; decreasing the number of awakeningsduring sleep; decreasing nocturnal arousals; decreasing the time spentawake following the initial onset of sleep; increasing the total amountof sleep; reducing the fragmentation of sleep; altering the timing,frequency or duration of REM sleep bouts; altering the timing, frequencyor duration of slow wave (i.e. stages 3 or 4) sleep bouts; increasingthe amount and percentage of stage 2 sleep; promoting slow wave sleep;enhancing EEG-delta activity during sleep; increasing daytime alertness;reducing daytime drowsiness; treating or reducing excessive daytimesleepiness; insomnia; hypersomnia; narcolepsy; interrupted sleep; sleepapnea; wakefulness; nocturnal myoclonus; REM sleep interruptions;jet-lag; shift workers' sleep disturbances; dyssomnias; night terror;insomnias associated with depression, emotional/mood disorders, as wellas sleep walking and enuresis, and sleep disorders which accompanyaging; Alzheimer's sundowning; conditions associated with circadianrhythmicity as well as mental and physical disorders associated withtravel across time zones and with rotating shift-work schedules,conditions due to drugs which cause reductions in REM sleep as a sideeffect; syndromes which are manifested by non-restorative sleep andmuscle pain or sleep apnea which is associated with respiratorydisturbances during sleep; and conditions which result from a diminishedquality of sleep.

Pain disorders for which the compounds of the invention may be usefulinclude neuropathic pain (such as postherpetic neuralgia, nerve injury,the “dynias”, e.g., vulvodynia, phantom limb pain, root avulsions,painful diabetic neuropathy, painful traumatic mononeuropathy, painfulpolyneuropathy); central pain syndromes (potentially caused by virtuallyany lesion at any level of the nervous system); postsurgical painsyndromes (eg, postmastectomy syndrome, postthoracotomy syndrome, stumppain); bone and joint pain (osteoarthritis), repetitive motion pain,dental pain, cancer pain, myofascial pain (muscular injury,fibromyalgia); perioperative pain (general surgery, gynecological),chronic pain, dysmennorhea, as well as pain associated with angina, andinflammatory pain of varied origins (e.g. osteoarthritis, rheumatoidarthritis, rheumatic disease, teno-synovitis and gout), headache,migraine and cluster headache, headache, primary hyperalgesia, secondaryhyperalgesia, primary allodynia, secondary allodynia, or other paincaused by central sensitization.

Compounds of the invention may also be used to treat or preventdyskinesias. Furthermore, compounds of the invention may be used todecrease tolerance and/or dependence to opioid treatment of pain, andfor treatment of withdrawal syndrome of e.g., alcohol, opioids, andcocaine.

The subject or patient to whom the compounds of the present invention isadministered is generally a human being, male or female, in whom M1allosteric modulation is desired, but may also encompass other mammals,such as dogs, cats, mice, rats, cattle, horses, sheep, rabbits, monkeys,chimpanzees or other apes or primates, for which treatment of the abovenoted disorders is desired.

The compounds of the present invention may be used in combination withone or more other drugs in the treatment of diseases or conditions forwhich the compounds of the present invention have utility, where thecombination of the drugs together are safer or more effective thaneither drug alone. Additionally, the compounds of the present inventionmay be used in combination with one or more other drugs that treat,prevent, control, ameliorate, or reduce the risk of side effects ortoxicity of the compounds of the present invention. Such other drugs maybe administered, by a route and in an amount commonly used therefor,contemporaneously or sequentially with the compounds of the presentinvention. Accordingly, the pharmaceutical compositions of the presentinvention include those that contain one or more other activeingredients, in addition to the compounds of the present invention. Thecombinations may be administered as part of a unit dosage formcombination product, or as a kit or treatment protocol wherein one ormore additional drugs are administered in separate dosage forms as partof a treatment regimen.

Examples of combinations of the compounds of the present inventioninclude combinations with anti-Alzheimer's Disease agents, for examplebeta-secretase inhibitors; alpha 7 nicotinic agonists, such as ABT089,SSR180711 and MEM63908; ADAM 10 ligands or activators; gamma-secretaseinhibitors, such as LY450139 and TAK 070; gamma secretase modulators;tau phosphorylation inhibitors; glycine transport inhibitors; LXR βagonists; ApoE4 conformational modulators; NR2B antagonists; androgenreceptor modulators; blockers of Aβ oligomer formation; 5-HT4 agonists,such as PRX-03140; 5-HT6 antagonists, such as GSK 742467, SGS-518,FK-962, SL-65.0155, SRA-333 and xaliproden; 5-HT1a antagonists, such aslecozotan; p25/CDK5 inhibitors; NK1NK3 receptor antagonists; COX-2inhibitors; HMG-CoA reductase inhibitors; NSAIDs including ibuprofen;vitamin E; anti-amyloid antibodies (including anti-amyloid humanizedmonoclonal antibodies), such as bapineuzumab, ACC001, CAD106, AZD3102,H12A11V1; anti-inflammatory compounds such as (R)-flurbiprofen,nitroflurbiprofen, ND-1251, VP-025, HT-0712 and EHT-202; PPAR gammaagonists, such as pioglitazone and rosiglitazone; CB-1 receptorantagonists or CB-1 receptor inverse agonists, such as AVE1625;antibiotics such as doxycycline and rifampin; N-methyl-D-aspartate(NMDA) receptor antagonists, such as memantine, neramexane and EVT101;cholinesterase inhibitors such as galantamine, rivastigmine, donepezil,tacrine, phenserine, ladostigil and ABT-089; growth hormonesecretagogues such as ibutamoren, ibutamoren mesylate, and capromorelin;histamine H₃ receptor antagonists such as ABT-834, ABT 829, GSK 189254and CEP16795; AMPA agonists or AMPA modulators, such as CX-717, LY451395, LY404187 and S-18986; PDE IV inhibitors, including MEM1414,HT0712 and AVE8112; GABA_(A) inverse agonists; GSK3β inhibitors,including AZD1080, SAR502250 and CEP16805; neuronal nicotinic agonists;selective M1 agonists; HDAC inhibitors; and microtubule affinityregulating kinase (MARK) ligands; or other drugs that affect receptorsor enzymes that either increase the efficacy, safety, convenience, orreduce unwanted side effects or toxicity of the compounds of the presentinvention.

Examples of combinations of the compounds include combinations withagents for the treatment of pain, for example non-steroidalanti-inflammatory agents, such as aspirin, diclofenac, duflunisal,fenoprofen, flurbiprofen, ibuprofen, indomethacin, ketoprofen,ketorolac, naproxen, oxaprozin, piroxicam, sulindac and tolmetin; COX-2inhibitors, such as celecoxib, rofecoxib, valdecoxib, 406381 and 644784;CB-2 agonists, such as 842166 and SAB378; VR-1 antagonists, such asAMG517, 705498, 782443, PAC20030, V114380 and A425619; bradykinin B1receptor antagonists, such as SSR240612 and NVPSAA164; sodium channelblockers and antagonists, such as VX409 and SPI860; nitric oxidesynthase (NOS) inhibitors (including iNOS and nNOS inhibitors), such asSD6010 and 274150; glycine site antagonists, including lacosamide;neuronal nicotinic agonists, such as ABT 894; NMDA antagonists, such asAZD4282; potassium channel openers; AMPA/kainate receptor antagonists;calcium channel blockers, such as ziconotide and NMED160; GABA-Areceptor IO modulators (e.g., a GABA-A receptor agonist); matrixmetalloprotease (MMP) inhibitors; thrombolytic agents; opioid analgesicssuch as codeine, fentanyl, hydromorphone, levorphanol, meperidine,methadone, morphine, oxycodone, oxymorphone, pentazocine, propoxyphene;neutrophil inhibitory factor (NIF); pramipexole, ropinirole;anticholinergics; amantadine; monoamine oxidase B15 (“MAO-B”)inhibitors; 5HT receptor agonists or antagonists; mGlu5 antagonists,such as AZD9272; alpha agonists, such as AGNXX/YY; neuronal nicotinicagonists, such as ABT894; NMDA receptor agonists or antagonists, such asAZD4282; NKI antagonists; selective serotonin reuptake inhibitors(“SSRI”) and/or selective serotonin and norepinephrine reuptakeinhibitors (“SSNRI”), such as duloxetine; tricyclic antidepressantdrugs, norepinephrine modulators; lithium; valproate; gabapentin;pregabalin; rizatriptan; zolmitriptan; naratriptan and sumatriptan.

The compounds of the present invention may be administered incombination with compounds useful for enhancing sleep quality andpreventing and treating sleep disorders and sleep disturbances,including e.g., sedatives, hypnotics, anxiolytics, antipsychotics,antianxiety agents, antihistamines, benzodiazepines, barbiturates,cyclopyrrolones, orexin antagonists, alpha-1 antagonists, GABA agonists,5HT-2 antagonists including 5HT-2A antagonists and 5HT-2A/2Cantagonists, histamine antagonists including histamine H3 antagonists,histamine H3 inverse agonists, imidazopyridines, minor tranquilizers,melatonin agonists and antagonists, melatonergic agents, other orexinantagonists, orexin agonists, prokineticin agonists and antagonists,pyrazolopyrimidines, T-type calcium channel antagonists,triazolopyridines, and the like, such as: adinazolam, allobarbital,alonimid, alprazolam, amitriptyline, amobarbital, amoxapine,armodafinil, APD-125, bentazepam, benzoctamine, brotizolam, bupropion,busprione, butabarbital, butalbital, capromorelin, capuride,carbocloral, chloral betaine, chloral hydrate, chlordiazepoxide,clomipramine, clonazepam, cloperidone, clorazepate, clorethate,clozapine, conazepam, cyprazepam, desipramine, dexclamol, diazepam,dichloralphenazone, divalproex, diphenhydramine, doxepin, EMD-281014,eplivanserin, estazolam, eszopiclone, ethchlorynol, etomidate, fenobam,flunitrazepam, flurazepam, fluvoxamine, fluoxetine, fosazepam,gaboxadol, glutethimide, halazepam, hydroxyzine, ibutamoren, imipramine,indiplon, lithium, lorazepam, lormetazepam, LY-156735, maprotiline,MDL-100907, mecloqualone, melatonin, mephobarbital, meprobamate,methaqualone, methyprylon, midaflur, midazolam, modafinil, nefazodone,NGD-2-73, nisobamate, nitrazepam, nortriptyline, oxazepam, paraldehyde,paroxetine, pentobarbital, perlapine, perphenazine, phenelzine,phenobarbital, prazepam, promethazine, propofol, protriptyline,quazepam, ramelteon, reclazepam, roletamide, secobarbital, sertraline,suproclone, TAK-375, temazepam, thioridazine, tiagabine, tracazolate,tranylcypromaine, trazodone, triazolam, trepipam, tricetamide,triclofos, trifluoperazine, trimetozine, trimipramine, uldazepam,venlafaxine, zaleplon, zolazepam, zopiclone, zolpidem, and saltsthereof, and combinations thereof, and the like, or the compound of thepresent invention may be administered in conjunction with the use ofphysical methods such as with light therapy or electrical stimulation.

In another embodiment, the subject compound may be employed incombination with levodopa (with or without a selective extracerebraldecarboxylase inhibitor such as carbidopa or benserazide),anticholinergics such as biperiden (optionally as its hydrochloride orlactate salt) and trihexyphenidyl (benzhexyl)hydrochloride, COMTinhibitors such as entacapone, MOA-B inhibitors, antioxidants, A2aadenosine receptor antagonists, cholinergic agonists and dopaminereceptor agonists such as alentemol, bromocriptine, fenoldopam,lisuride, naxagolide, pergolide and pramipexole.

The term “composition” as used herein is intended to encompass a productcomprising specified ingredients in predetermined amounts orproportions, as well as any product which results, directly orindirectly, from combination of the specified ingredients in thespecified amounts. This term in relation to pharmaceutical compositionsis intended to encompass a product comprising one or more activeingredients, and an optional carrier comprising inert ingredients, aswell as any product which results, directly or indirectly, fromcombination, complexation or aggregation of any two or more of theingredients, or from dissociation of one or more of the ingredients, orfrom other types of reactions or interactions of one or more of theingredients.

In general, pharmaceutical compositions are prepared by uniformly andintimately bringing the active ingredient into association with a liquidcarrier or a finely divided solid carrier or both, and then, ifnecessary, shaping the product into the desired formulation. In thepharmaceutical composition the active compound, which is a compound offormulae (I) to (IX), is included in an amount sufficient to produce thedesired effect upon the process or condition of diseases. Accordingly,the pharmaceutical compositions of the present invention encompass anycomposition made by admixing a compound of the present invention and apharmaceutically acceptable carrier.

The carrier may take a wide variety of forms depending on the form ofpreparation desired for administration, e.g., oral or parenteral(including intravenous). Thus, the pharmaceutical compositions of thepresent invention can be presented as discrete units suitable for oraladministration such as capsules, cachets or tablets each containing apredetermined amount of the active ingredient. Further, the compositionscan be presented as a powder, as granules, as a solution, as asuspension in an aqueous liquid, as a non-aqueous liquid, as anoil-in-water emulsion or as a water-in-oil liquid emulsion. In additionto the common dosage forms set out above, the compounds of theinvention, or pharmaceutically acceptable salts thereof, may also beadministered by controlled release means and/or delivery devices.

Pharmaceutical compositions intended for oral use may be preparedaccording to any method known to the art for the manufacture ofpharmaceutical compositions and such compositions may contain one ormore agents selected from the group consisting of sweetening agents,flavoring agents, coloring agents and preserving agents in order toprovide pharmaceutically palatable preparations. Tablets may contain theactive ingredient in admixture with non-toxic pharmaceuticallyacceptable excipients which are suitable for the manufacture of tablets.These excipients may be, for example, inert diluents, such as calciumcarbonate, sodium carbonate, lactose, calcium phosphate or sodiumphosphate; granulating and disintegrating agents, for example, cornstarch, or alginic acid; binding agents, for example starch, gelatin oracacia, and lubricating agents, for example magnesium stearate, stearicacid or talc. The tablets may be uncoated or they may be coated by knowntechniques to delay disintegration and absorption in thegastrointestinal tract and thereby provide a sustained action over alonger period.

A tablet containing the composition of this invention may be prepared bycompression or molding, optionally with one or more accessoryingredients or adjuvants. Compressed tablets may be prepared bycompressing, in a suitable machine, the active ingredient in afree-flowing form such as powder or granules, optionally mixed with abinder, lubricant, inert diluent, surface active or dispersing agent.Molded tablets may be made by molding in a suitable machine, a mixtureof the powdered compound moistened with an inert liquid diluent. Eachtablet preferably contains from about 0.1 mg to about 500 mg of theactive ingredient and each cachet or capsule preferably containing fromabout 0.1 mg to about 500 mg of the active ingredient.

Compositions for oral use may also be presented as hard gelatin capsuleswherein the active ingredient is mixed with an inert solid diluent, forexample, calcium carbonate, calcium phosphate or kaolin, or as softgelatin capsules wherein the active ingredient is mixed with water or anoil medium, for example peanut oil, liquid paraffin, or olive oil.

Other pharmaceutical compositions include aqueous suspensions, whichcontain the active materials in admixture with excipients suitable forthe manufacture of aqueous suspensions. In addition, oily suspensionsmay be formulated by suspending the active ingredient in a vegetableoil, for example arachis oil, olive oil, sesame oil or coconut oil, orin a mineral oil such as liquid paraffin. Oily suspensions may alsocontain various excipients. The pharmaceutical compositions of theinvention may also be in the form of oil-in-water emulsions, which mayalso contain excipients such as sweetening and flavoring agents.

The pharmaceutical compositions may be in the form of a sterileinjectable aqueous or oleaginous suspension, or in the form of sterilepowders for the extemporaneous preparation of such sterile injectablesolutions or dispersions. In all cases, the final injectable form mustbe sterile and must be effectively fluid for easy syringability. Thepharmaceutical compositions must be stable under the conditions ofmanufacture and storage; thus, preferably should be preserved againstthe contaminating action of microorganisms such as bacteria and fungi.

Pharmaceutical compositions of the present invention can be in a formsuitable for topical use such as, for example, an aerosol, cream,ointment, lotion, dusting powder, or the like. Further, the compositionscan be in a form suitable for use in transdermal devices. Theseformulations may be prepared via conventional processing methods. As anexample, a cream or ointment is prepared by mixing hydrophilic materialand water, together with about 5 wt % to about 10 wt % of the compound,to produce a cream or ointment having a desired consistency.

Pharmaceutical compositions of this invention can also be in a formsuitable for rectal administration wherein the carrier is a solid. It ispreferable that the mixture forms unit dose suppositories. Suitablecarriers include cocoa butter and other materials commonly used in theart.

By “pharmaceutically acceptable” it is meant the carrier, diluent orexcipient must be compatible with the other ingredients of theformulation and not deleterious to the recipient thereof.

The terms “administration of” or “administering a” compound should beunderstood to mean providing a compound of the invention to theindividual in need of treatment in a form that can be introduced intothat individual's body in a therapeutically useful form andtherapeutically useful amount, including, but not limited to: oraldosage forms, such as tablets, capsules, syrups, suspensions, and thelike; injectable dosage forms, such as IV, IM, or IP, and the like;transdermal dosage forms, including creams, jellies, powders, orpatches; buccal dosage forms; inhalation powders, sprays, suspensions,and the like; and rectal suppositories.

The terms “effective amount” or “therapeutically effective amount” meansthe amount of the subject compound that will elicit the biological ormedical response of a tissue, system, animal or human that is beingsought by the researcher, veterinarian, medical doctor or otherclinician.

As used herein, the term “treatment” or “treating” means anyadministration of a compound of the present invention and includes (1)inhibiting the disease in an animal that is experiencing or displayingthe pathology or symptomatology of the diseased (i.e., arresting furtherdevelopment of the pathology and/or symptomatology), or (2) amelioratingthe disease in an animal that is experiencing or displaying thepathology or symptomatology of the diseased (i.e., reversing thepathology and/or symptomatology).

The compositions containing compounds of the present invention mayconveniently be presented in unit dosage form and may be prepared by anyof the methods well known in the art of pharmacy. The term “unit dosageform” is taken to mean a single dose wherein all active and inactiveingredients are combined in a suitable system, such that the patient orperson administering the drug to the patient can open a single containeror package with the entire dose contained therein, and does not have tomix any components together from two or more containers or packages.Typical examples of unit dosage forms are tablets or capsules for oraladministration, single dose vials for injection, or suppositories forrectal administration. This list of unit dosage forms is not intended tobe limiting in any way, but merely to represent typical examples of unitdosage forms.

The compositions containing compounds of the present invention mayconveniently be presented as a kit, whereby two or more components,which may be active or inactive ingredients, carriers, diluents, and thelike, are provided with instructions for preparation of the actualdosage form by the patient or person administering the drug to thepatient. Such kits may be provided with all necessary materials andingredients contained therein, or they may contain instructions forusing or making materials or components that must be obtainedindependently by the patient or person administering the drug to thepatient.

When treating or ameliorating a disorder or disease for which compoundsof the present invention are indicated, generally satisfactory resultsare obtained when the compounds of the present invention areadministered at a daily dosage of from about 0.1 mg to about 100 mg perkg of animal body weight, preferably given as a single daily dose or individed doses two to six times a day, or in sustained release form. Thetotal daily dosage is from about 1.0 mg to about 2000 mg, preferablyfrom about 0.1 mg to about 20 mg per kg of body weight. In the case of a70 kg adult human, the total daily dose will generally be from about 7mg to about 1,400 mg. This dosage regimen may be adjusted to provide theoptimal therapeutic response. The compounds may be administered on aregimen of 1 to 4 times per day, preferably once or twice per day.

The amount of active ingredient that may be combined with the carriermaterials to produce a single dosage form will vary depending upon thehost treated and the particular mode of administration. For example, aformulation intended for the oral administration to humans mayconveniently contain from about 0.005 mg to about 2.5 g of active agent,compounded with an appropriate and convenient amount of carriermaterial. Unit dosage forms will generally contain between from about0.005 mg to about 1000 mg of the active ingredient, typically 0.005,0.01 mg, 0.05 mg, 0.25 mg, 1 mg, 5 mg, 25 mg, 50 mg, 100 mg, 200 mg, 300mg, 400 mg, 500 mg, 600 mg, 800 mg or 1000 mg, administered once, twiceor three times a day.

It will be understood, however, that the specific dose level andfrequency of dosage for any particular patient may be varied and willdepend upon a variety of factors including the activity of the specificcompound employed, the metabolic stability and length of action of thatcompound, the age, body weight, general health, sex, diet, mode and timeof administration, rate of excretion, drug combination, the severity ofthe particular condition, and the host undergoing therapy.

Several methods for preparing the compounds of this invention areillustrated in the schemes and examples herein. Starting materials aremade according to procedures known in the art or as illustrated herein.The following examples are provided so that the invention might be morefully understood, and are not to be construed as limiting the scope ofthe invention in any manner.

Intermediate A: (5-Bromopyridin-3-yl)methanol

A solution of 5-bromonicotinic acid (6.65 g, 32.9 mmol) in 75 mL of MeOHwas heated to reflux for 4 hours, cooled to room temperature, andconcentrated in vacuo. The residue was diluted with aqueous sodiumbicarbonate and EtOAc, and the organic fraction was washed with brine,dried, filtered, and concentrated in vacuo to provide crude methyl5-bromonicotinate. To a solution of the above compound in 100 mL of THFat −70° C. was added LAH (1 M in THF, 0.036 mL, 0.036 mmol). After 1hour, 1 mL of water and 1 mL 1 N NaOH were added, followed by 2 mL ofaqueous ammonium chloride. The mixture was diluted with ether and sodiumsulfate, filtered, and concentrated in vacuo to provide the titlecompound as a yellow oil.

Intermediate B: 5-Bromo-2-(bromomethyl)pyrimidine

A solution of 5-bromo-2-iodopyrimidine (5.00 g, 17.6 mmol) in 25 mL ofTHF was cooled to 0° C. under nitrogen. Dimethyl zinc (2.0 M in toluene,13.2 mL, 26.3 mmol) and palladium tetrakis (5 mol %) were added. After 5hours, aqueous ammonium chloride (5 mL) was added, and the reactionmixture was warmed to room temperature. The mixture was diluted withethyl acetate (30 mL) and washed with aqueous sodium bicarbonate (2×30mL) and brine (30 mL). The combined organic extracts were dried,filtered and concentrated in vacuo to provide 5-bromo-2-methylpyridinethat gave a proton NMR spectra consistent with theory and a mass ion(ES+) of 173.1 for M+H⁺(⁷⁹Br).

To a solution of the above compound (3.40 g, 19.6 mmol) in 100 mL ofCCl₄ (25 mL) was added N-bromosuccinimide (6.98 g, 39.2 mmol) and2,2′-azobisisobutyronitrile (2.30 g, 14.0 mmol). The reaction was heatedto 100° C. for 24 hours, then cooled to room temperature and washed withaqueous sodium bicarbonate and brine. The organic layer was dried oversodium sulfate, filtered, and concentrated. The crude material wassubjected to chromatography on silica gel eluting with 0-5% EtOAc inhexanes to yield the title compound as a pale yellow needles which gavea proton NMR spectrum consistent with theory and a mass ion (ES+) of252.8 for M+H⁺.

Intermediate C: (5-Chloropyrzin-2-yl)methanol

A solution of 5-chloropyrazine-2-carbaldehyde (5.20 g, 36.5 mmol) in 50mL of methanol was cooled to 0° C. Sodium borohydride (1.45 g, 38.3mmol) was added and the reaction mixture was allowed to stir at ambienttemperature for 3 hour. Saturated aqueous ammonium chloride (5 mL) wasadded, and the methanol was removed in vacuo. The resulting residue wasdissolved in ethyl acetate (50 mL) and washed with aqueous sodiumbicarbonate (2×50 mL) and brine (50 mL).

The combined organic extracts were dried, filtered and concentrated invacuo to provide the title compound that gave a proton NMR spectraconsistent with theory.

Intermediate D: (6-Chloropyridazin-3-yl)methyl methanesulfonate

To a suspension of 6-chloropyridazine-3-carbaldehyde (2.50 g, 17.5 mmol)in 30 mL of methanol (30 mL) at 0° C. was added sodium borohydride (0.26g, 7.02 mmol). The reaction mixture was warmed to room temperature.After 2 hours, the reaction mixture was concentrated in vacuo andtriturated with 20% MeOH in dichloromethane to provide(6-chloropyridazin-3-yl)methanol.

To a solution of the above compound (0.30 g, 2.07 mmol) andtriethylamine (0.87 mL, 6.23 mmol) in 5 mL of dichloromethane (5 mL) at0° C. was added methanesulfonyl chloride (0.32 mL, 4.15 mmol) dropwise.The reaction was stirred for 20 minutes and concentrated in vacuo toprovide the title compound that gave a mass ion (ES+) of 223.2 for M+H⁺.

Example 15-{6-[(3-Carboxy-8-fluoro-4-oxoquinolin-1(4H)-yl)methyl]pyridine-3-yl}-2-fluoropyridinium

A solution of (5-bromo-pyridin-2-yl)-methanol (20.0 g, 106 mmol) in 150mL of dichloromethane was cooled to 0° C. under nitrogen. Triethylamine(19.3 mL, 138 mmol) was added, followed by methanesulfonyl chloride(9.95 ml, 128 mmol). After 2.5 hours, the mixture was quenched with 50mL of water and diluted with 100 mL of dichloromethane. The organiclayer was washed with an additional 50 mL of water and then the aqueouslayer was extracted with 100 mL of methylene chloride. The organicextracts were dried over sodium sulfate, filtered and concentrated toprovide (5-bromopyridin-2-yl)methyl methanesulfonate as a red solid thatgave a proton NMR spectra consistent with theory and a mass ion (ES+) of268.1 for M+H⁺(⁸¹Br).

To a solution of ethyl-8-fluoro-4-oxo-1,4-dihydroquinoline-3-carboxylate(5.00 g, 21.3 mmol) in 50 mL of DMF under nitrogen was added the abovecompound (8.48 g, 31.9 mmol), potassium iodide (0.176 g, 1.06 mmol), andpotassium carbonate (3.53 g, 25.5 mmol). The reaction mixture wasstirred at 60° C. for 15 hours, cooled to room temperature, and dilutedwith 200 mL of water. The resulting solid was washed with water (2×100mLl) and diethyl ether (2×75 mL) and dried in vacuo to provide ethyl1-[(5-bromopyridin-2-yl)methyl]-8-fluoro-4-oxo-1,4-dihydroquinoline-3-carboxylatethat gave a proton NMR spectra consistent with theory and a mass ion(ES+) of 407.0 for M+H⁺(⁸¹Br).

To a solution of the above compound (7.28 g, 17.97 mmol) in 40 mL ofdioxane was added aqueous saturated LiOH to pH ˜10.5. After 24 hours,the mixture was acidified with 1 N HCl to pH 4. The resulting solid waswashed with water (3×80 mL) and dried in vacuo to provide1-[(5-bromopyridin-2-yl)methyl]-8-fluoro-4-oxo-1,4-dihydroquinoline-3-carboxylicacid that gave a proton NMR spectra consistent with theory and a massion (ES+) of 379.0 for M+H⁺(⁸¹ Br).

To a solution of the above compound (0.200 g, 0.530 mmol),2-fluoropyridine-5-boronic acid (0.082 g, 0.583 mmol), and 1 N cesiumcarbonate (1.06 ml, 1.06 mmol) in 2 mL THF under nitrogen was addedbis(tri-tert-butyl-phosphine)palladium(0) (10 mol %). The mixture washeated for 10 minutes in the microwave at 160° C. The reaction wascooled to room temperature, and additionalbis(tri-tert-butyl-phosphine)palladium(0) (10 mol %) was added. Themixture was heated again for 10 minutes in the microwave at 160° C.,then cooled to room temperature and stirred overnight with Quadrapure TUresin. The sample was filtered with methanol (10 mL) and concentrated invacuo. The resulting residue was purified via reverse phase HPLC toprovide the title compound which gave a proton NMR consistent withtheory and a mass ion (ES+) of 394.0 for M+H⁺. ¹H NMR (400 MHz, DMSO) δ9.21 (s, 1H), 8.79 (d, J=1.7 Hz, 1H), 8.59 (d, J=2.6 Hz, 1H), 8.33 (dt,J=8.2 Hz, 2.6 Hz, 1H), 8.27 (dd, J=8.1 Hz, 1.0 Hz, 1H), 8.21 (dd, J=8.2Hz, 2.4 Hz, 1H), 7.74 (m, 1H), 7.65-7.58 (m, 2H), 7.31 (dd, J=8.6 Hz,2.6 Hz, 1H), 6.09 (d, J=4.0, 2H).

Example 2 Ethyl1-{[5-(1-ethyl-1H-pyrazol-4-yl)pyridin-2-yl]methyl}-5,8-difluoro-4-oxo-1,4-dihydroquinoline-3-carboxylate

To a solution of ethyl1-[(5-bromopyridin-2-yl)methyl]-5,8-difluoro-4-oxo-1,4-dihydroquinoline-3-carboxylate(3.00 g, 7.09 mmol), tert-butyl4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-carboxylate(5.42 g, 18.4 mmol), and 1 N cesium carbonate (14.2 mL, 14.2 mmol) in 50mL of THF under nitrogen was addedbis(tri-tert-butylphosphoranyl)palladium (10 mol %). The reactionmixture was heated to 100° C. for 20 hours, then cooled to roomtemperature. Ethyl acetate (100 mL) and water (100 mL) were added, andthe resultant brown solid was collected to provide ethyl5,8-difluoro-4-oxo-1-{[5-(1H-pyrazol-4-yl)pyridin-2-yl]methyl}-1,4-dihydroquinoline-3-carboxylatethat gave a proton NMR spectra consistent with theory and a mass ion(ES+) of 411.0 for M+H⁺.

To a solution of the above compound (0.100 g, 0.244 mmol) in 1 mL of DMFwas added sodium hydride (0.010 g, 0.26 mmol) and ethylbromide (0.053 g,0.49 mmol). After 1.5 hours, 1 N NaOH (0.40 mL, 0.40 mmol) was added andthe reaction was stirred for an additional 16 hours. The reactionmixture was acidified with 6 N HCl to pH ˜2, diluted with ethyl acetate(30 mL), and washed with aqueous sodium bicarbonate (2×30 mL) and brine(30 mL). The organic extract was dried, filtered and concentrated invacuo to provide the title compound which gave a proton NMR spectrumconsistent with theory and a mass ion (ES+) of 411.0 for M+H⁺: ¹H NMR(400 MHz, d⁶-DMSO) δ 9.35 (s, 1H), 8.90 (s, 1H), 8.46 (s, 1H), 8.20-8.17(m, 2H), 8.14 (s, 1H), 8.00-7.93 (m, 1H), 7.65-7.59 (m, 2H), 6.18 (s,2H), 4.35 (q, J=7.1 Hz, 2H), 1.60 (t, J=7.1 Hz, 3H).

Example 35,8-difluoro-1-{[2-(1H-imidazol-1-yl)pyridin-4-yl]methyl}-4-oxo-1,4-dihydroquinoline-3-carboxylicacid

In a 0.5-2 mL Emrys™ process vial, a mixture of the1-[(2-bromopyridin-4-yl)methyl]-5,8-difluoro-4-oxo-1,4-dihydroquinoline-3-carboxylicacid (0.015 g, 0.37 mmol), imidazole (0.035 g, 0.52 mmol), cesiumcarbonate (0.241 g, 0.740 mmol), racemictrans-N,N′-dimethylcyclohexane-1,2-diamine (5.3 mg, 0.037 mmol), copper(I) iodide (0.704 mg, 0.0037 mmol) and 1-methyl-2-pyrrolidinone (1.8 mL)were combined, purged with a stream of nitrogen and heated via EmrysOptimizer™ microwave to 100° C. for 30 minutes. The mixture was cooledto room temperature, filtered, and concentrated in vacuo. The resultingresidue was purified via reverse phase HPLC to provide the titlecompound as the trifluoroacetate salt, which gave a proton NMR spectrumconsistent with theory and a high resolution mass spectrum (ES+) m/z of383.0976 calculated for M+H⁺[C₁₉H₁₂F₂N₄O₃: 383.095]: ¹H NMR (500 MHz,DMSO-d6) δ 14.76 (bs, CO₂H), 9.36 (bs, 1H), 9.16 (s, 1H), 8.54 (d, J=5.4Hz, 1H), 8.26 (bs, 1H), 7.72-7.78 (m, 2H), 7.60 (bs, 1H), 7.38-7.44 (m,2H), 6.01 (s, 2H).

The compounds in Table 1 below (of formula (II)) were prepared accordingto the general procedure provided in Examples 1-3. The startingmaterials are either commercially available or may be prepared fromcommercially available reagents using conventional reactions well knownto those skilled in the art.

TABLE 1 4-Oxo-1,4-Dihydroquinoline Compounds of General Formula (II)LRMS/HRMS Example R¹ R² R³ (M + H⁺) 4 F H

393.0 5 F H

392.1 6 F H

406.1 7 F H

394.1 8 F H

406.1 9 F H

419.1 10 F H

391.1 11 F H

379.1 12 F H

365.1 13 F H

390.1 14 F H

390.1 15 F H

377.1 16 F H

391.1 17 F H

394.1 18 F H

410.1 19 F H

406.1 20 F H

394.1 21 F H

410.1 22 F H

390.1 23 F H

406.1 24 F H

394.1 25 F H

470.1 26 F H

390.1 27 F H

461.2 28 F H

390.1 29 F H

410.1 30 F H

394.1 31 F H

436.1 32 F H

406.0 33 F H

382.0 34 F H

395.0 35 F H

394.1 36 F H

455.1 37 F H

418.1 38 F H

426.1 39 H F

375.1 40 H F

379.1 41 H F

418.1 42 H F

376.1 43 H F

394.1 44 H F

393.1 45 H F Me N/A 46 H F

443.1 47 H F

414.1 48 H F Br 377.0 49 H F

391.1 50 H F

443.0 51 H F

405.1 52 H F

365.1 53 H F

453.1 54 H F

391.1 55 H F

390.1 56 H F

459.1 57 H F

418.2 58 H F

403.1 59 H F

394.1 60 H F

381.1 61 H F

381.1 62 H F

431.1 63 H F

389.1 64 H F

419.1 65 H F

459.1 66 H F

418.2 67 H F

376.1 68 H F

365.1 69 H F

379.1 70 H F

365.1 71 H F

N/A 72 H F

417.1 73 H F

443.1 74 H F

426.1 75 H F

432.1 76 H F

433.1 77 H F

443.1 78 H F

417.1 79 H F

447.1 80 H F

432.1 81 H F

412.1 82 H F

431.1 83 H F

406.1 84 H F

468.1 85 H F

432.1 86 H F

406.1 87 H F

511.1 88 H F

391.1 89 H F

417.1 90 H F

450.1 91 H F

403.1 92 H F Me 313.1 93 H F

432.0 94 H F

379.0 95 H F

390.1 96 H F

400.1 97 H F

389.1 98 H F

405.1 99 H F

453.0 100 H F

453.0 101 H F

468.1 102 H F

405.1 103 H F

459.1 104 H F

400.1 105 H F

389.1 106 H F

409.1 107 H F

403.1 108 H F

411.0 109 F F

446.1 110 F F

432.1 111 F F

449.1 112 F F

444.1 113 F F

413.1 114 F F

383.1 115 F F

412.1 116 F F

383.1 117 F F

424.1 118 F F

454.1 119 F F

462.0 120 F F

428.1 121 F F

428.1 122 F F

479.2 123 F F

412.1 124 F F

428.1 125. F F

462.1 126 F F

446.1 127 F F

432.1 128 F F

449.1 129 F F

444.1 130 F F

413.1 131 F F

383.1 132 F F

412.1 133 F F

383.1 134 F F

424.1 135 F F

454.1 136 F F

462.0 137 F F

428.1 138 F F

428.1 139 F F

479.2 140 F F

412.1 141 F F

428.1 142 F F

462.1 143 F F

357.1 144 F F Et 345.1 145 F F

408.0 146 F F

400.0 147 F F

397.1 148 F F

427.9 149 F F

410.9 150 F F

424.0 151 F F

418.9 152 F F

411.0 153 F F

423.0 154 F F

432.9 155 F F

424.9 156 F F

464.9 157 F F

446.9 158 F F

408.0

The compounds in Table 2 below (of General Formula (V)) were preparedaccording to the general procedure provided in Examples 1-3. Thestarting materials are either commercially available or may be preparedfrom commercially available reagents using conventional reactions wellknown to those skilled in the art.

TABLE 2 4-Oxo-1,4-Dihydroquinoline Compounds of General Formula (V)Exam- LRMS/HRMS ple R^(3A) R^(3B) (M + H⁺) 159

H 474.1   160

H 383.0   161

H 433.0   162

H 383.1   163

H 434.0   164

H 397.0   165

H 393.0   166 H

383.1   167 H

383.1   168 H

393.0   169 H

397.1   170

H 408.1   171

H 450.1253 172

H 437.0939 173

H 451.1095 174

H 444.1157 175

H 432.1151 176

H 492.1749 177

H 408.1176 178

H 408.1161 179

H 450.1254 180

H 486.0933 181

H 486.0926 182

H 450.1262 183

H 486.0930 184

H 412.1106 185

H 395.0955 186

H 432.1152 187

H 412.0906 188

H 446.1306 189

H 444.1162 190

H 383.0957 191

H 409.1120 192

H 411.1267 193

H 436.1477 194

H 479.1537 195

H 436.1473 196

H 422.1318 197

H 436.1467 198

H 394.1010 199

H 409.0993 200

H 409.0997 201

H 409.0997 202

H 412.0910 203

H 412.0910 204

H 412.0905 205

H 428.0622 206

H 428.0616 207

H 428.0608 208

H 428.0609 209

H 424.1112 210

H 424.1122 211

H 410.0965 212

H 412.0922 213

H 410.1067

The compounds in Table 3 below (of General Formula (III)) were preparedaccording to the general procedure provided in Examples 1-3. Thestarting materials are either commercially available or may be preparedfrom commercially available reagents using conventional reactions wellknown to those skilled in the art.

TABLE 3 4-Oxo-1,4-Dihydroquinoline Compounds of General Formula (III)Exam- LRMS/HRMS ple R¹ R^(3A) R^(3B) (M + H⁺) 214 H Cl H 333.1 215 H

H 375.1 216 H

H 376.1 217 H

H 418.2 218 H

H 393.1 219 H

H 443.1 220 H

H 444.1 221 H

H  436.13 222 H

H  426.13 223 H

H  410.07 224 H

H  461.16 225 H

H  393.11 226 H

H  459.10 227 H

H  511.09 228 H

H  381.07 229 H

H  381.07 230 H

H  426.13 231 H

H  390.12 232 H

H  468.10 233 H

H  393.14 234 H

H  428.14 235 H

H 392.1 236 H

H  459.10 237 H

H  411.10 238 H

H  431.09 239 H

H  418.16 240 H

H  390.13 241 H

H  432.14 242 H

H  468.10 243 H

H  418.16 244 H

H  390.13 245 H

H  432.14 246 H

H  406.12 247 H

H  419.15 248 H

H  394.10 249 H

H 365.1 250 H

H 376.0 251 H

H 394.1 252 H

H 406.1 253 H

H 391.1 254 H

H 421.0 255 256 H

H 379.0 257 F H H N/A 258 F

H 393.9 259 F

H 446.1 260 F

H 427.9 261 F

H 439.0 262 F

H 397.0 263 F

H 410.9 264 F

H 478.9 265 F

H 423.9 266 F

H 422.9 267 F

H 408.0 268 F

H 435.9 269 F

H 411.9 270 F

H 423.9 271 F

H 427.9 272 F

H 395.9 273 F

H 436.9 274 F H

383.0 275 F H

397.0 276 F H

393.0 277 278 F H

383.1 279 F H

433.0

Compound 277 is a mixture of two isomers (as depicted for the R^(3B)group).

The compounds in Table 4 below were prepared according to the generalprocedure provided in Examples 1-3. The starting materials are eithercommercially available or may be prepared from commercially availablereagents using conventional reactions well known to those skilled in theart.

TABLE 4 4-Oxo-1,4-Dihydroquinoline Compounds Exam- LRMS/HRMS ple R¹ R²R³ (M + H⁺) 280 H F

413.9 281 F F

431.9 282 H H

396.0 283 H F

335.2 284 F F

383.1 285 F F

383.1 286 F F

474.1 287 F F

397.1 288 F F

393.1 289 F F

433.1 290 F F

433.1 291 F H

313.2

The compounds in Table 5 (of General Formula (VI)) below were preparedaccording to the general procedure provided in Examples 1-3. Thestarting materials are either commercially available or may be preparedfrom commercially available reagents using conventional reactions wellknown to those skilled in the art.

TABLE 5 4-Oxo-1,4-Dihydroquinoline Compounds of General Formula (VI)LRMS/HRMS Example R³ (M + H⁺) 292

392.1 293

392.1 294

376.1 295

419.2 296

377.1 297

377.1 298

394.1 299

444.0 300

444.1 301

366.1 302

406.1 303

390.1 304

382.0 305

394.1 306

427.1 307 H?   300.07865

The compounds in Table 6 below (of General Formula (VII)) were preparedaccording to the general procedure provided in Examples 1-3. Thestarting materials are either commercially available or may be preparedfrom commercially available reagents using conventional reactions wellknown to those skilled in the art.

TABLE 6 4-Oxo-1,4-Dihydroquinoline Compounds of General Formula (VII)LRMS/HRMS Example R³ (M + H⁺) 308 Cl 334.1 309

392.1 310

454.1 311

366.1 312

444.1 313

444.1 314

444.1 315

377.1 316

377.1 317

376.1

The compounds in Table 7 below (of General Formula (VIII)) were preparedaccording to the general procedure provided in Examples 1-3. Thestarting materials are either commercially available or may be preparedfrom commercially available reagents using conventional reactions wellknown to those skilled in the art.

TABLE 7 4-Oxo-1,4-Dihydroquinoline Compounds of General Formula (VIII)LRMS/HRMS Example R³ (M + H⁺) 318

427.1 319

392.1 320

376.1 321

419.1 322

377.1 323

377.0 324

394.1 325

444.1 326

366.0 327

390.1 328

382.0 329

394.1 330

415.1 331

392.1 332

383.1 333

369.1 334

355.1 335

385.1 336

401.1 337 NMe₂ 343.1 338 OMe 330.1 339 OEt 344.1 340 OCH₂CF₃ 398.1 341OCH₂CHF₂ 380.1 342 CN 401.1 343 SMe 346.1 344

401.1 345

401.1 346

406.1 347

444.0 348

406.1 349

406.1 350

394.0 351 SO₂Me 378.1 352 SOMe 362.1 353

366.1 354

367.1 355

367.1 356

390.1 357

454.1 358

454.1 359

465.1 360

378.1 361

392.1 362

376.1

The compounds in Table 8 below (of General Formula (IX)) were preparedaccording to the general procedure provided in Examples 1-3. Thestarting materials are either commercially available or may be preparedfrom commercially available reagents using conventional reactions wellknown to those skilled in the art.

TABLE 8 4-Oxo-1,4-Dihydroquinoline Compounds of General Formula (IX)LRMS/HRMS Example R³ (M + H⁺) 363

380.1 364

419.2 365

377.1 366

377.1 367

377.1 368

395.1 369

394.1 370

412.1 371

444.1 372

406.1 373

392.1

Example 3728-Fluoro-4-oxo-1-[(6-piperidin-1-ylpyridazin-3-yl)methyl]-1,4-dihydroquinoline-3-carboxylicacid

To a solution of1-[(6-chloropyridazin-3-yl)methyl]-8-fluoro-4-oxo-1,4-dihydroquinoline-3-carboxylicacid (0.040 g, 0.12 mmol) in 1 mL of DMSO was added piperidine (0.015mL, 0.16 mmol). The reaction mixture was irradiated in the microwave at100° C. for 10 minutes, and purified via reverse phase HPLC to providethe title compound that gave a proton NMR spectra consistent with theoryand a mass ion (ES+) of 383.1 for M+H⁺.

Example 3738-Fluoro-1-{[6-(methylsulfonyl)pyridazin-3-yl]methyl}-4-oxo-1,4-dihydroquinoline-3-carboxylicacid

To a solution of1-[(6-chloropyridazin-3-yl)methyl]-8-fluoro-4-oxo-1,4-dihydroquinoline-3-carboxylicacid (0.050 g, 0.15 mmol) in 1 mL of DMSO was added sodium thiomethoxide(0.032 g, 45 mmol). The reaction mixture was irradiated in the microwaveat 100° C. for 10 minutes, and purified via reverse phase HPLC toprovide8-fluoro-1-{[6-(methylthio)pyridazin-3-yl]methyl}-4-oxo-1,4-dihydroquinoline-3-carboxylicacid that gave a proton NMR spectra consistent with theory and a massion (ES+) of 346.1 for M+H⁺.

To a solution of the above compound in 1 mL of MeOH was added oxone(0.160 g, 0.261 mmol) dissolved in 0.5 mL of water. After 1 hour, thereaction mixture was poured into water (15 mL) and extracted with ethylacetate (3×15 mL). The combined organics were washed with brine (15 mL),dried over sodium sulfate, filtered, and concentrated in vacuo. Theresidue was purified via reverse phase HPLC to provide8-fluoro-1-{[6-(methylsulfinyl)pyridazin-3-yl]methyl}-4-oxo-1,4-dihydroquinoline-3-carboxylicacid that gave a proton NMR spectra consistent with theory and a massion (ES+) of 362.1 for M+H⁺, and the title compound that gave a protonNMR spectra consistent with theory and a mass ion (ES+) of 378.1 forM+H⁺.

M1 Receptor Positive Allosteric Modulator Properties

The utility of the compounds as M1 receptor positive allostericmodulators may be demonstrated by methodology known in the art,including by the assay described below. The assay is designed to selectcompounds that possess modulator activity at the acetylcholinemuscarinic M1 receptor or other muscarinic receptors expressed inCHOnfat cells by measuring the intracellular calcium with a FLIPR³⁸⁴Fluorometric Imaging Plate Reader System. The assay studies the effectof one or several concentrations of test compounds on basal oracetylcholine-stimulated Ca²⁺ levels using FLIPR.

Compounds are prepared and subjected to a preincubation period of 4 min.Thereafter, a single EC₂₀ concentration of acetylcholine is added toeach well (3 nM final). The intracellular Ca²⁺ level of each sample ismeasured and compared to an acetylcholine control to determine anymodulatory activity.

Cells: CHOnfat/hM1, hM2, hM3 or hM4 cells are plated 24 hr before theassay at a density of 18,000 cells/well (100 μL) in a 384 well plate.CHOnfat/hM1 and CHOnfat/hM3 Growth Medium: 90% DMEM (Hi Glucose); 10% HIFBS; 2 mM L-glutamine; 0.1 mM NEAA; Pen-Strep; and 1 mg/ml Geneticin,are added. For M2Gqi5CHOnfat and M4Gqi5CHOnfat cells, an additional 600μg/ml hygromycin is added.

Equipment: 384 well plate, 120 μL addition plate; 96-well Whatman 2 mlUniplate Incubator, 37C, 5% CO₂; Skatron EMBLA-384 Plate Washer;Multimek Pipetting System; Genesis Freedom 200 System; Mosquito System;Temo Nanolitre Pipetting System; and FLIPR³⁸⁴ Fluorometric Imaging PlateReader System are used.

Buffers. Assay Buffer: Hanks Balanced Salt Solution, with 20 mM Hepes,2.5 mM Probenecid (Sigma P-8761) first dissolved in 1N aqueous NaOH, 1%Bovine Serum Albumin (Sigma A-9647). Dye Loading Buffer: Assay Bufferplus 1% Fetal Bovine Serum and Fluo-4AM/Pluronic Acid Mixture. 2 mMFluo-4AM ester stock in DMSO (Molecular Probes F-14202) Concentration of2 μM in buffer for a final concentration of 1 μM in Assay. 20% PluronicAcid Solution stock, with a concentration of 0.04% in Buffer, 0.02% inAssay.

65 μL of 2 mM Fluo-4AM are mixed with 130 μL of 20% Pluronic Acid. Theresulting solution and 650 μL FBS is added to the assay buffer for atotal volume of 65 mL. Positive Controls: 4-Br-A23187: 10 mM in DMSO;final concentration 10 μM. Acetylcholine: 10 mM in water, working stockat both 20 μM and 30 μM in assay buffer, final concentration of 10 μM.This is used to check the maximum stimulation of the CHOK1/hM1 cells. 20μM (2×) acetylcholine is added in the preincubation part of the assay,and the 30 μM (3×) stock is added in the second part.(EC₂₀)Acetylcholine: 10 mM in water, working stock of 9 nM (3×), andfinal concentration in assay is 3 nM. This is used after thepreincubation with test compounds. Addition of the EC₂₀ Acetylcholine toeach well with a test compound will ascertain any modulator activity. 24wells contain 3 nM Acetylcholine alone as a control.

Determining Activity of Putative Compounds:

Screening Plate Compounds are titrated in 96-well plates (columns 2-11),100% DMSO, started at a concentration of 15 mM (150× stockconcentration), and 3-fold serial dilutions using Genesis Freedom200System. Four 96-well plates are combined into a 384-well plate usingMosquito Nanolitre Pipetting System by transferring 1 μl of serialdiluted compounds to each well, and 1 mM acetylcholine (100× stockconcentration) were added as a control. Using Temo, 49 μl assay bufferis added to each well of the 384-well plate right before assay.

In a 96-well Whatman 2 ml Uniplate, 9 nM Acetylcholine (3×) is pipettedinto wells corresponding to the screening compounds, and into controlwells. The 30 μM acetylcholine control (3×) is added into control wells,and the 3× agonist plate is transferred into a 384-well plate.

Cells are washed three times with 100 μL, of buffer, leaving 30 μL ofbuffer in each well. Using Multimek, 30 μL of Dye Loading Buffer isadded into each well and incubated at 37° C., 5% CO₂ for up to one hr.

After 60 min, the cells are washed three times with 100 μL of buffer,leaving 30 μL of buffer in each well. The cell plate, screening plate,and agonist addition plates are placed on the platform in the FLIPR andthe door is closed. A signal test to check background fluorescence andbasal fluorescence signal is performed. Laser intensity is adjusted ifnecessary.

4 min of preincubation with the test compounds is provided to determineany agonist activity on the M1 receptor by comparison to the 1 mMacetylcholine control. After preincubation, the EC₂₀ value ofacetylcholine (3 nM final) is added to determine any modulator activity.

A further description of the muscarinic FLIPR assay can be found inInternational patent application WO2004/073639.

In particular, the compounds of the following examples had activity inthe aforementioned assay, generally with an IP (inflection point) of 30μM (30,000 nM) or less. The inflection point is calculated from theFLIPR values, and is a measure of activity. Such a result is indicativeof the intrinsic activity of the compounds in as M1 allostericmodulators.

IP values from the aforementioned assay for representative exemplarycompounds of the invention (as described herein) are provided below inTable 9 below:

IP Value Example (nM) 1 202 2 65 7 495 10 103 11 176 25 220 27 100 43202 55 24 68 1900 75 131 101 99 108 745 134 302 156 114 160 2241 216 951234 37 283 2888 293 2324 315 7190 319 382 329 8662 334 5248 352 24820362 4000 365 1442 372 14280 373 ~80000

The following abbreviations are used throughout the text:

-   -   Me: methyl    -   Et: ethyl    -   t-Bu: tert-butyl    -   Ar: aryl    -   Ph: phenyl    -   Bn: benzyl    -   BOC: t-butyloxycarbonyl    -   LAM: lithium aluminum hydride    -   DMF: dimethylformamide    -   HMDS: hexamethyldisilazane    -   THF: tetrahydrofuran    -   Ac: acetyl or acetate    -   DMSO: dimethylsulfoxide    -   DMEM: Dulbecco's Modified Eagle Medium (High Glucose)    -   FBS: fetal bovine serum    -   rt: room temperature    -   aq: aqueous    -   HPLC: high performance liquid chromatography    -   MS: mass spectrometry    -   LRMS: low resolution mass spectrometry    -   HRMS: high resolution mass spectrometry

While the invention has been described and illustrated with reference tocertain particular embodiments thereof, those skilled in the art willappreciate that various adaptations, changes, modifications,substitutions, deletions, or additions of procedures and protocols maybe made without departing from the spirit and scope of the invention. Itis intended, therefore, that the invention be defined by the scope ofthe claims that follow and that such claims be interpreted as broadly asis reasonable.

1-22. (canceled)
 23. A compound of formula (I):

or a pharmaceutically acceptable salt thereof, wherein one or two of X¹,X², X³, X⁴ and X⁵ is NH, and the others are each CR³; R¹ and R² are eachselected from the group consisting of (1) hydrogen, or (2) fluoro; R³ isselected from the group consisting of (1) hydrogen, (2) halogen, (3)cyano, (4) —C₁₋₆-alkyl, (5) —OC₁₋₆-alkyl, (6) —C₃₋₈ cycloalkyl, (7)—C₆₋₁₀ aryl, (8) heteroaryl group having 5 to 12 ring atoms, (9)—NR^(6A)R^(6B), (10) —S(O)_(m)—R^(5A), wherein any alkyl, aryl,heteroaryl, and cycloalkyl R³ moiety is optionally substituted with oneor more (a) halogen, (b) hydroxy, (c) cyano, (d) —(CH₂)_(q)-aryl, (e)—O—C₁₋₆ alkyl, (f) —C₁₋₆ alkyl, (g) —(CH₂)_(p)—NR^(6C)R^(6D), (h) —C₃₋₈cycloalkyl, (i) heteroaryl group having 5 to 12 ring atoms, (j)—C(═O)—OR^(5A), (k) —C(═O)—R^(5A), (l) —S(O)_(m)—R^(5A), (m)—C(═O)—NR^(6A)R^(6B), (n) —NR^(5A)SO₂—R^(5B), (o) —NR^(5A)C(═O)R^(5B),(p) —NR^(5A)C(═O)—O—R^(5B), and wherein said alkyl, aryl or heteroarylmoiety is optionally substituted with one or more (i) halogen, (ii)hydroxy, or (iii) cyano; R⁴ is selected from the group consisting of (1)hydrogen, (2) —C₁₋₆ alkyl, and (3) —CH₂-aryl, wherein said R³ alkyl oraryl moiety is optionally substituted with one or more (a) halogen, (b)cyano, and (c) —O—C₁₋₆ alkyl, wherein said alkyl is optionallysubstituted with one or more halo; R^(5A) and R^(5B) are independentlyselected from the group consisting of (1) hydrogen, (2) —C₁₋₆ alkyl, and(3) —(CH₂)_(n)-aryl, wherein said R^(5A) or R^(5B) alkyl or aryl moietyis optionally substituted with one or more (a) halogen, (b) cyano, and(c) —O—C₁₋₆ alkyl, wherein said alkyl is optionally substituted with oneor more halo; R^(6A), R^(6B), R^(6C) and R^(6D) are selected from thegroup consisting of (1) hydrogen, (2) —C₁₋₆ alkyl, (3) —C₁₋₆ cycloalkyl,or R^(6A) and R^(6B), or R^(6C) and R^(6D) are linked together with thenitrogen to which they are both attached to form a 3-6 memberedcarbocyclic ring, wherein one or two of the ring carbon atoms isreplaced by a nitrogen, oxygen or sulfur; m is 0, 1 or 2; n is 0 or 1; pis 0 or 1; and q is 0 or
 1. 24. A compound of claim 23, or apharmaceutically acceptable salt thereof, wherein one of X¹, X², X³, X⁴and X⁵ is NH, and the others are each CR³.
 25. A compound of claim 23,or a pharmaceutically acceptable salt thereof, wherein two of X¹, X²,X³, X⁴ and X⁵ is NH, and the others are each CR³.
 26. A compound ofclaim 23, or a pharmaceutically acceptable salt thereof, wherein R³ isselected from the group consisting of (1) hydrogen, (2) —C₆₋₁₀ aryl, or(3) a heteroaryl group having 5 to 12 ring atoms.
 27. A compound ofclaim 26, or a pharmaceutically acceptable salt thereof, wherein when R³is aryl or heteroaryl, the aryl or heteroaryl moiety is substituted withone or more (a) halogen, (b) cyano, (c) —O—C₁₋₆ alkyl, wherein the alkylis optionally substituted with one or more fluoro, (d) —C₁₋₆ alkyl,wherein the alkyl is optionally substituted with one or more fluoro, (e)—NR^(6C)R^(6D), (f) —C(═O)—OR^(5A), (g) —C(═O)—R^(5A), (h)—S(O)_(m)—R^(5A), (i) —C(═O)—NR^(6A)R^(6B), (j) —NR^(5A)SO₂—R^(5B), (k)—NR^(5A)C(═O)R^(5B), or (l) —NR^(5A)C(═O)—O—R^(5B).
 28. A compound ofclaim 23, or a pharmaceutically acceptable salt thereof, wherein one ofR¹ and R² is fluoro and the other is hydrogen.
 29. A compound of claim23, or a pharmaceutically acceptable salt thereof, wherein R¹ and R² areeach fluoro.
 30. A compound of claim 23, or a pharmaceuticallyacceptable salt thereof, wherein R¹ and R² are both hydrogen.
 31. Acompound of any of claim 23, or a pharmaceutically acceptable saltthereof, wherein R⁴ is hydrogen.
 32. A compound of claim 23, or apharmaceutically acceptable salt thereof, wherein the compound offormula (I) is a compound of formula (II):

or a pharmaceutically acceptable salt thereof, wherein R¹, R², R³ and R⁴are as defined in claim
 23. 33. A compound of claim 23, wherein thecompound of formula (I) is a compound of formula (III):

or a pharmaceutically acceptable salt thereof, wherein R¹, R² and R⁴ areas defined in claim 1, and R^(3A) and R^(3B) are selected from the samegroup as R³.
 34. A compound of claim 23, wherein the compound of formula(I) is a compound of formula (IV):

or a pharmaceutically acceptable salt thereof, wherein R¹, R², R³ and R⁴are as defined in claim
 1. 35. A compound of claim 23, wherein thecompound of formula (I) is a compound of formula (V):

or a pharmaceutically acceptable salt thereof, wherein R¹, R² and R⁴ areas defined in claim 1, and R^(3A) and R^(3B) are selected from the samegroup as R³.
 36. A compound of claim 23, wherein the compound of formula(I) is a compound of formula (VI):

or a pharmaceutically acceptable salt thereof, wherein R¹, R², R³ and R⁴are as defined in claim
 1. 37. A compound of claim 23, wherein thecompound of formula (I) is a compound of formula (VII):

or a pharmaceutically acceptable salt thereof, wherein R¹, R², R³ and R⁴are as defined in claim
 1. 38. A compound of claim 23, wherein thecompound of formula (I) is a compound of formula (VIII):

or a pharmaceutically acceptable salt thereof, wherein R¹, R², R³ and R⁴are as defined in claim
 1. 39. A compound of claim 23, wherein thecompound of formula (I) is a compound of formula (IX):

or a pharmaceutically acceptable salt thereof, wherein R¹, R², R³ and R⁴are as defined in claim
 1. 40. A pharmaceutical composition comprising atherapeutically effective amount of a compound of any of claim 23, or apharmaceutically acceptable salt thereof, and a pharmaceuticallyacceptable carrier.
 41. A pharmaceutical composition for the treatmentof a disease or disorder mediated by the muscarinic M1 receptor, whereinsaid disease or disorder is selected from the group consisting ofAlzheimer's disease, schizophrenia, pain or sleep disorders, comprisinga therapeutically effective amount of a compound of claim 23, or apharmaceutically acceptable salt thereof, and a pharmaceuticallyacceptable carrier.
 42. Use of a pharmaceutical composition of claim 23for the treatment of a disease or disorder mediated by the muscarinic M1receptor, wherein said disease or disorder is selected from the groupconsisting of Alzheimer's disease, schizophrenia, pain or sleepdisorders.
 43. Use of a compound of claim 23, or a pharmaceuticallyacceptable salt thereof, and a pharmaceutically acceptable carrier, forthe manufacture of a medicament for the treatment of a disease ordisorder mediated by the muscarinic M1 receptor, wherein said disease ordisorder is selected from the group consisting of Alzheimer's disease,schizophrenia, pain or sleep disorders.
 44. A method of treating adisease or disorder mediated by the muscarinic M1 receptor, wherein saiddisease or disorder is selected from the group consisting of Alzheimer'sdisease, schizophrenia, pain or sleep disorders in a patient in needthereof, comprising administering to the patient a therapeuticallyeffective amount of a compound of claim 23, or a pharmaceuticallyacceptable salt thereof, and a pharmaceutically acceptable carrier.